STRUGGLE WITH BONZAI: A REVIEW ON SYNTHETIC CANNABINOID ABUSE
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89
Received: 17.08.2014 - Accepted: 28.08.2014
STRUGGLE WITH BONZAI: A REVIEW ON SYNTHETIC CANNABINOID ABUSE
Şeyda Ece Sarıbaş1, Ahmet Ulugöl2
Trakya University, Faculty of Medicine, Edirne, TURKEY
1
Department of Medicinal Pharmacology, Trakya University Faculty of Medicine, Edirne, TURKEY
2
ABSTRACT
Cannabis has been a widely favored recreational drug throughout history. It has also been used as me-
dicine, due to its analgesic and anti-inflammatory effects. Following the discovery of its main ingredient, Δ9-tet-
rahydrocannabinol (THC), studies focused on synthesizing new cannabinoids to be used in medicine. However,
possessing the highly demanded qualities of a recreational drug, synthetic cannabinoids are nowadays being
marketed as safe, natural and legal alternatives of cannabis around the world. Turkey is one of the countries in
which these synthetic cannabinoids are readily available and the rate of abuse continues to increase. This review
focuses on these misperceptions, examining the acute and long-term effects of synthetic cannabis abuse in ad-
dition to the medical and forensic advancements necessary to prevent this growing trend of cannabinoid abuse.
Key Words: Endocannabinoids, cannabinoid, receptors, tetrahydrocannabinol, cannabis abuse, recreational
drugs, cannabis-related disorder, psychotic disorders, schizophrenia, substance abuse detection
INTRODUCTION anti-inflammation (4). Although cannabis itself has
no definitively accepted medical value, its synthetic
Cannabis sativa, or marijuana, as named in derivatives are benefited from in certain medical con-
Western societies, or hashish, a more widely used ditions (5). Dronabinol, levonantradol, (whose use
name in Eastern cultures, is a plant which both dates has later been discontinued) and nabilone are such
far back in history and is still as popular and widely derivatives of THC and are used in conditions such
used as it has been thousands of years ago as a recrea- as neuropathic syndromes, chemotherapy-induced
tional drug (1). Earliest use of cannabis by humans has nausea and spasticity in multiple sclerosis, generally
been discovered in Taiwan, in an ancient village disco- after all other possible medications have been tried
vered by archeologists and dates back over 10,000 ye- and exhausted (5, 6). Despite being used in a control-
ars into the Stone Age (2). Since then, it has continued led manner as a medication, those compounds have
to attract attention due to its recreational effects and revealed psychotomimetic side effects similar to tho-
the possibility of a medical use along with its poten- se of cannabis, such as loss of control and anxiety (6).
tial to be abused. However, it was not until 1964 that Researches for eliminating the undesirable side effects
Mechoulam and Gaoni (3) configured the chemical while preserving the analgesic and anti-inflammatory
structure of the plant. It was understood that althou- nature of cannabis, led to a breakthrough in synthe-
gh multiple chemical structures were available in the sis of synthetic cannabinoids, starting with John W.
plant, Δ9-tetrahydrocannabinol (THC) was the actual Huffman, professor of emeritus at Clemson Univer-
psychoactive component causing the high demand for sity, USA. Beginning in 1980s, his main focus was
cannabis. Indeed, this quality of THC has been shown on synthesizing new cannabinoids which would have
to decrease brain-stimulation reward thresholds (1), properties similar to those of THC. Huffman named
explaining the pleasurable nature of cannabis and re- and numbered the compounds he synthesized after his
peating substance-seeking behavior seen afterwards. initials, such as JWH-018 and JWH-205 (7, 8). What
Besides its abuse, cannabis has also been used for is now, for almost a decade, known as synthetic can-
medical purposes throughout the history, some of its nabinoids or “legal highs” has arised from Huffman’s
most frequently preferred effects being analgesia and work outside legal research facilities, which Huffman
Adress for Correspondence: Şeyda Ece Sarıbaş, Trakya University Faculty of Medicine, Edirne, Turkey - e-mail: seydasaribas@hotmail.com
90
calls “hijacking of basic research”. He states that this is wish legal consequences to follow (13). In 2013, the
neither the first nor the last time that a substance de- largest survey ever conducted on synthetic cannabino-
veloped legitimately through scientific discovery has id users revealed that when given a chance, users pre-
been abused (7). fer classic cannabis over synthetic cannabinoids, sta-
ting that classic cannabis was more enjoyable in terms
Emergence of synthetic cannabinoids as of experienced pleasure, that their cognitive functions
recreational substances were more efficient after classic cannabis uptake and
synthetic cannabinoids caused unpleasant hangovers
Synthetic cannabinoids used outside of scien- compared to classic cannabis (14). Such substances are
tific research presented themselves first in Germany known to be readily obtained via internet, gas stations,
in 2004 as recreational drugs (9). Sold as herbal incen- so called “headshops” mostly in Europe or even on the
ses, they are advertised to be the legal, nontoxic and street in some countries.
natural alternatives to cannabis (5, 10, 11). Marketed
under brand names such as Spice and K2 (K2 being Another reason for being popular is that synt-
named after the second-highest mountain on Earth), hetic cannabinoids are advertised to be and perceived
exotically and colorfully decorated packages contain a as natural herbs. The actual production method, alt-
“not for human consumption” label but are consumed hough not very clear, is hypothesized as the synthesis
for their cannabimimetic affects (see Figure 1). Due of cannabinoids, dissolution of the synthesized subs-
to the rapid increase in synthetic cannabinoid abuse, tance in solvent and the mixing procedure which con-
sufficient data in terms of its pharmacological and sists of spraying different kinds of dry plant leaves with
toxicological aspects has not yet been gathered (5). the mixture. After the solvent evaporates, what rema-
However, as the number of medical cases affected by ins behind is the leaves loaded with synthetic cannabi-
synthetic cannabinoids increases, so does the concern noid (15). One other significant aspect is the fact that
regarding public health. Researches involving adoles- because there is no definitive evidence as to which
cents show that despite a dramatic decrease in alcohol chemical compounds are found in synthetic cannabi-
and tobacco use, there is a high demand for synthetic noid mixtures, there is no drug screening developed to
cannabinoids (12). A number of reasons could explain detect such substances of abuse in body fluids. It is hy-
this phenomenon. First reason why synthetic cannabi- pothesized that some compounds might have different
noids are widely used is that they are advertised to be psychostimulating effects or are added to the blend just
natural herbal blends, legally produced and served to to make it more challenging to identify which specific
public. Patient interviews reveal that those who prefer type of synthetic cannabinoid is the main ingredient
synthetic cannabinoids over classic cannabis seek to in a given package (11). These circumstances further
experience the desired effects of cannabis but do not add to the perception that synthetic cannabinoids are
safe for regular use (5, 6, 13). Yet, this is not the case.
Undeclared substances in these blends, possibly many
times stronger than cannabis (16), lead synthetic can-
nabinoids to present a growing public health problem
in the ways that they affect human body with not only
its psychotic effects but also by causing psychosis and
impaired cognitive function (6, 17, 18-28), addiction,
cytotoxicity of forebrain (29), cannabinoid hypereme-
sis syndrome (30), withdrawal syndrome (31), kidney
injuries (13), cardiac arrests (32) and even deaths (due
to disruption of physiologic processes or suicide com-
mitted in a synthetic cannabinoid-induced state) (5).
Medical professionals are not fully equipped to handle
acute and long term outcomes of synthetic cannabino-
id abuse due to two main reasons: i) Effects of synthe-
tic cannabinoids on humans have never been studied
in a controlled scientific research. Even though series
of cases have been published, there is no assertive
Figure 1: Samples of so-called herbal blends. data as to what changes occur in human physiology91
at a certain amount of synthetic cannabinoids intake. These complications are much more likely to occur in
ii) THC content varies in different mixtures, thus the the presence of synthetic cannabinoids, which are full
studies to examine the dose-response relationship are agonists of CB1 and CB2 receptors and have been pro-
to be further complicated (6). Due to the preparation ven to be hundreds of times potent compared to THC
technique described above, synthetic cannabinoids are (15). Because the chemical composition varies, so
likely to be unevenly distributed in marketed herbal does these effects and their durations, making it more
incenses, resulting in unpredictable effects and an inc- problematic for health professionals to handle acute
reased risk of overdosing (5). intoxications (9).
Mechanism of action, desired effects leading There has never been the chance to conduct
to abuse and long-term results controlled studies examining the effects of cannabino-
ids on humans, as stated above. But Compton et al.
Two types of cannabinoid receptors have been (35) have studied the effects of CB1 receptor agonists
defined up to date, named cannabinoid-1 (CB1) and on laboratory animals and defined the phenomenon
cannabinoid-2 (CB2) receptors. CB1 receptors are which is now named as the cannabinoid tetrad. The
abundant on presynaptic terminals in central nervous study revealed that the organism responded to the
system and function via retrograde signaling, where- CB1 agonist intake with hypothermia, analgesia, cata-
as CB2 receptors are primarily available in tissues in- lepsy and locomotor suppression. These results obta-
volved in immune activities, such as lymphocytes and ined with cannabis became more drastic as the expe-
bone marrow (1, 5, 15). Analgesic and anti-inflamma- riment was performed with JWH-018 and JWH-073,
tory properties of cannabis result from the dispersal of two substances most frequently detected in synthetic
CB1 and CB2 receptors in human body, respectively. herbal blends.
Defined as the target of THC, these receptors are actu-
ally a significant part of the endocannabinoid system, These findings bring scientists to this questi-
which is crucial in homeostasis. Endocannabinoids on: In what way do synthetic cannabinoids differ from
are defined as endogenous ligands which activate CB1 classic cannabis so that they end up resulting in more
and CB2 receptors in order to regulate physiological severe side effects? In addition to the higher affinity
processes such as cognitive functions, immunity and they have towards CB1 receptors (15), it is specula-
pain modulation (33). Seeing as these receptors play a ted that synthetic cannabinoids may also be acting on
crucial role in homeostasis, it is not unusual that can- non-cannabinoid receptors. Furthermore, classic can-
nabis and its derivatives cause a variety of systemic ef- nabis contains substances named “terpenoids”, which
fects, be it desired or unfavorable (5). help increase the desired effects of THC while redu-
cing the unpleasant side effects. However, no such re-
Primary way of cannabinoid intake, be it clas- gulating substance have been come across in synthetic
sic cannabis or synthetic cannabinoids, is inhalation blends, which thus cause more dramatic results than
but ingestion is also not rare (9). Smoking enables the classic cannabis (5).
substances to be absorbed quickly through lungs, whi-
ch is a matter of seconds. Because cannabinoids are hi- It would seem paradoxical for a substance
ghly lipophilic, they are readily absorbed by fat tissues used for its euphoric effects to result in toxicity and
and more importantly, neural tissues (34). long-term manifestations which might be irreversib-
le, but regarding synthetic cannabinoid abuse, this is
Following THC exposure, which acts as a par- the case. Ibrahim et al. (32) describes a case of cardi-
tial agonist especially on CB1 receptors, GABAergic ac arrest in a patient who has been a long time user
neurons are suppressed, resulting in the cessation of of cannabis but has recently started using the blends
inhibitory mechanisms on dopaminergic neurons named K2. It is reported that the arrest occurred wit-
(1, 5, 15). The desired effects of cannabinoids occur hin an hour of substance use. The direct relationship
following these alterations in metabolism, such as between the abused substance and cardiac problems is
euphoria and altered perception. Yet, the unwanted derived from the fact that there was evidence of myo-
side effects such as anxiety, hallucinations, delusions, cardial necrosis (elevated troponin T and CKMB le-
cognitive impairment and somatic effects such as ta- vels), though no coronary occlusion which might have
chycardia, nausea-vomiting, cardiac arrhythmias and caused the necrosis could be found. Furthermore, as
kidney injuries also follow through these mechanisms. the patient stopped abusing synthetic cannabinoids,92
no recurring cardiac problems took place. In additi- grows stronger (25). Gaffuri et al. (26) approach the
on to cardiac manifestations, series of cases suffering situation from the view that because the CB1 receptors
from nephrotoxicity as a result of synthetic cannabi- and their activity modulated by endocannabinoids are
noid abuse have been reported, presenting themselves invaluable to neural development which starts in utero
with nausea, abdominal/flank pain and dangerously and continues to 20s, an interference of psychoactive
elevated creatinine levels along with no other possible stimulants such as THC to this development might in-
pathology to explain the renal injury (9, 13). Tomiya- terrupt this process.
ma and Funada (29) have shown the cytotoxic effect
of synthetic cannabinoids in brain tissue cultures is The results of cannabinoid abuse on cogni-
mediated through CB1 receptors and that this effe- tive function has been examined in various studies.
ct occurs via apoptosis. Although there has been no Tramèr et al. state that cannabinoid administration to
study to examine the cytotoxicity of synthetic canna- patients with chemotherapy-induced nausea and vo-
binoids on other tissues, this mechanism might be the miting caused an increase in their risk of developing
fact underlying organ pathologies following synthetic depression and paranoia. (19) Andréasson et al. (20)
cannabinoid abuse. examined more than 45,000 males aged 18-20 during
a time interval of 15 years in terms of cannabino-
Considering that the main target of cannabi- id abuse and hospitalization for psychotic disorders.
noids is the nervous system, it can be anticipated that The result stated that the risk of developing schizoph-
the most severe long-term results of cannabinoid abu- renia increases significantly even in those who have
se arise from neurologic and psychiatric dysfunctions. used cannabis only once in their lifetime, proving that
Along with the acute effects such as hallucinations and cannabis abuse is an independent risk factor for sc-
disorientation, long-term effects of cannabinoids have hizophrenia. Compton and Broussard (18) found that
also raised concern among healthcare professionals. the risk of developing acute psychosis increases signi-
Acute effects of cannabinoids are presumed to be mo- ficantly in those who consume classic herbal cannabis
dified by genetic factors and personality traits, there- on a daily basis compared to non-daily consumers. A
fore it is observed that only a fraction of cannabinoid birth cohort involving 1265 children in New Zealand
abusers undergo psychotic disorders. Nevertheless, (21) showed that those who use cannabis daily have a
evidence also suggests that early and heavy exposure 2.3 to 3.3fold increased risk of psychosis compared to
to cannabis can result in an elevated risk for develo- non-abusers. Solowij et al. (22) showed that the me-
ping psychotic outcomes, the most critical one being mory impairment continues in heavy cannabis users
schizophrenia (6). Schizophrenia is known to be one even after the acute toxic phase. Fontes and Balla (23)
of the most serious psychotic disorders. Although still studied cognitive performance in chronic cannabis
a hypothesis, the fluctuating dopamine levels are con- users in groups whose cannabis abuse started before
sidered significant in schizophrenia (36), which might and after the age 15. The result is that although both
possibly relate to the CB1-dopamine activity explai- groups showed dysfunction, those who started youn-
ned above. ger than 15 have greater cognitive impairment. One of
the most striking studies in this area has been condu-
Studies indicate that the risk of developing ps- cted by Meier and Caspi (24), revealing that chronic
ychotic symptoms is related to the age of onset of can- cannabis abuse is significantly related to a decline in
nabis abuse, a family history of psychotic disorders, a IQ, which cannot be entirely reversed even after the
history of childhood abuse and genetic structure. The cannabis abuse has been terminated.
age of exposure seems to be the most important factor
because adolescence is the time interval in which ner- Patient and family history have also been pro-
vous system is highly susceptible to damage from out- ven to be significant. In a study involving more than 2
side. On the other hand, the fact that a greater number million patients, Arendt et al. (27) showed that having
of cases developing psychotic symptoms are aged 25 or a family history of schizophrenia translates into a sig-
younger brings up the question whether cannabinoids nificant increase in the risk of developing cannabis-in-
actually aggravate a pre-existing prodromal phase of a duced psychosis. Another study revealed that sexual
certain psychotic pathology. Arseneault et al. point out or physical abuse in childhood increases the canna-
that such an early onset is risky because it both incre- bis-induced psychosis risk (28).
ases the risk of developing schizophrenia and the pro-
bability that the cannabinoid abuse will be long-lasting93
Cannabinoid Hyperemesis Syndrome is cer- ongoing seizure causing muscle spasms, blood levels
tainly an intriguing phenomenon caused by chronic of CPK and myoglobin should also be determined to
cannabis consumption. First described by Allen et al. be cautious against a possible rhabdomyolysis. As with
(37) in 2004 in a series of cases, it is defined as per- opioids, antipsychotics should be used cautiously, as
sistent abdominal pain, nausea and vomiting among it may lower seizure threshold of the patient, further
chronic cannabis users, where chronic stands for can- complicating the situation (12, 40).
nabis use at least once every week. An urge to take hot
showers/baths several times a day also accompanies. Synthetic cannabinoid abuse in Turkey:
It is hypothesized that because CB1 receptors in the A growing epidemic
brain are very close to hypothalamus, chronic stimula-
tion of these receptors may cause irregulations in hy- As the so called synthetic cannabinoid in-
pothalamic thermoregulation. Therefore, the urge to dustry extends around the world, the number of sy-
take hot showers may be the way the body tries to op- nthetic cannabinoid abusers also increases. Turkey,
pose this change in thermal regulation (38). It would in that respect, is no exception. Turkey is a country
seem contradictory that cannabis and its derivatives, where narcotic plants such as opium can be cultiva-
despite being used as anti-emetic agents in cases such ted and the use of such recreational substances dates
as chemotherapy-induced nausea, can cause emesis back to 10th century. It is known that the country is
itself. Although the pathophysiology has not been il- exposed to an intense drug trafficking, in which sy-
luminated, it is hypothesized that the stimulation of nthetic cannabinoids are transported from Europe to
CB1 receptors can cause peristaltic movements to ce- Asia while opiates follow the opposite route (41). Press
ase, resulting in emesis. Because there are no defini- shows great interest in cases where adolescents found
tive drug screening tests for synthetic cannabinoids, overdosed on streets, people intoxicated by cannabi-
it may very well be a challenge to diagnose Cannabi- noids or how easily these products can be obtained.
noid Hyperemesis Syndrome, presuming the patient Official records show that these products were captu-
is not honest about substance abuse. All categories of red the first time in 2010 with the most frequent ing-
antiemetics can be administered as treatment. Volume redient being JWH-018. The names on the packages
depletion is a significant situation to take precautions were and still are different from Spice and K2, which
for and when untreated, may cause prerenal failure. are more widely used in Europe. “Bonzai Aromatic Po-
Opioid analgesics against persistent abdominal pain tpourri”, “Bonzai Plant Growth Regulator”, “Jamaican
should be carefully administered, as it might potentia- Gold”, “Heaven”, “Yukatan Fire”, “Smoke XXX”, “Aro-
te the side effects of cannabinoids already available in matic Incense” are few of the market names of these
the tissues (30). products (see Figure 2). Tracking the internet, it is evi-
dent that these synthetic cannabinoids are accessible to
Synthetic Cannabinoid Withdrawal Syndro- young population of every age. Several websites excite
me, described by Haney in 2005 (39), is the solid proof and encourage people into buying these herbal blends,
that cannabinoids, be it classic cannabis or synthetic which are, similar to the rest of the world, often refer-
cannabinoids, have the capacity to be significantly ad- red as herbal incenses not for human use. However,
dictive. A less common outcome of chronic cannabis the data obtained from Istanbul Narcotic Department
abuse, the symptoms range from irritability to anxiety, of the Council of Forensic Medicine, Turkey, reveals
loss of appetite and an urge for cannabis intake (31, that this is not the case. Herbal compounds other than
39). Despite the fact that cannabis and its synthetic classical cannabis, captured and analyzed between Au-
derivatives possess all the aspects of an addictive subs- gust 2010 and March 2012, revealed that 98,3% of the
tance including a withdrawal syndrome, they are still blends contained synthetic cannabinoids (16). Even
advertised to be non-addictive recreational drugs. though most of these familiar synthetic cannabinoi-
ds such as JWH-018 are illegal in Turkey, there is no
Last issue to discuss regarding synthetic can- regulation against their derivatives to be synthesized
nabinoids should be what treatment should be ad- and abused.
ministered if cannabinoid toxicity is suspected. It is
recommended to run a complete blood count and
metabolic panel, and cardiac enzymes if chest pain is
among the complaints of the patient. Lorazepam is re-
commended for agitation and seizures. If there is an94
analysis methods to detect these substances are ne-
cessary, along with the need for increased public awa-
reness. Only then it would be possible to obviate this
ever-growing health risk.
Ethics Committee Approval: N/A
Informed Consent: N/A
Conflict of Interest: The authors declared no conflict of
interest.
Financial Disclosure: The authors declared that this study
received no financial support.
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